Prolonged and sustained endogenous stimulation is a factor which promotes the development of thyroid cancer in rats maintained on a low iodine diet. It is also well established that most of the metabolic activities of the thyroid are mediated through cAMP including protein synthesis leading to hyperplasia. More recent evidence suggests that cAMP may act as a "growth pattern modificator" for a number of neoplastic cell lines maintained in vitro. In addition, the work of Ney et al. points to a possible defect in hormonal sensitivity of the adenylcyclase (AC) system of endocrine neoplastic tissue exemplified by the spontaneous rat adrenocortical cancer. There are, however, no data indicating that TSH induced thyroid tumors in animal models, and for that matter in humans are indeed generated through a mechanism which implies excessive stimulation or lack of stimulation (due to aberrations of receptor sites) of AC-cAMP system. The purpose of this investigation is to determine the role of AC and its functional antagonist cyclic phosphodiesterase (cPDEase) in TSH dependent cancer of the thyroid. This will be achieved by studying sequentially the two enzymatic markers, AC and cPDEase activity, in experimentally induced TSH dependent thyroid cancer in the rat by combined biochemical and histochemical methods with the hope of demonstrating that the stimulus governing neoplastic proliferation is or is not conveyed through the AC-cAMP system. Parallel to experimental work, the same enzymatic markers will be studied in human cases of thyroid cancer and also in adenomas or nodules of the human thyroid known to have precancerous potentials. By utilizing a morpho-physiologic approach, we intend to bring, in addition, better understanding of the intracellular structure associated distribution of these enzymes in normal and in hyperplastic conditions. If our working hypothesis is correct, the present investigation may open the door to a possible control of neoplastic processes in hormone dependent endocrine cancer.